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In Vivo DNA Cross-Linking by Cyclophosphamide: Comparison of Human Chronic Lymphatic Leukemia Cells with Mouse L1210 Leukemia and Normal Bone Marrow Cells¹

Wayne State University School of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, Detroit, Michigan 48201 [W. D., F. V., C. E., M. B.]; and the Veterans Administration Medical Center, Allen Park, Michigan 48101 [M. E.]

Alkaline elution was done on a variety of cells following cyclophosphamide (CY) treatment in vivo. Cells used were L1210 leukemia, normal mouse bone marrow, and peripheral blood cells obtained from a patient with chronic lymphatic leukemia (CLL). Endpoints used were determination of single strand breaks, DNA-DNA interstrand and DNA-protein cross-links.

After treatment of mice with CY (4 mg/mouse), low levels of single strand breaks were observed in both L1210 leukemia and CDF₁ normal bone marrow. When a patient with CLL was treated with CY (750 mg/m²), no evidence of single strand breaks could be demonstrated.

Maximum levels of DNA-DNA interstrand cross-links were observed in mice 2 h after injection of CY for the L1210 leukemia cells [175 ± 25 rad-equivalents (req)] and at 4 h for the CDF₁ normal bone marrow cells (47 ± 9 req). In human CLL, maximum levels were observed 12 h after injection of CY. Peak levels of DNA-DNA interstrand cross-links were approximately 4-fold lower in CDF₁ normal bone marrow cells than in L1210 leukemia. The frequencies measured in human CLL cells were relatively low at any timepoint (mean at 12 h = 36 req).

Maximum levels of DNA-protein cross-links were observed 4 h after injection of CY (4 mg/mouse) for both L1210 leukemia [123 req (mean)] and normal bone marrow cells [50 req (mean)]. DNA-protein cross-links were measurable in CLL at timepoints later than 4 h after the start of injection of CY. In order to obtain equitoxicity between L1210 leukemia and CDF₁ normal bone marrow cells, about 18-fold higher doses of CY had to be given than in the case of the normal bone marrow cells. In contrast, only 4-fold higher doses had to be given to the normal bone marrow to obtain equivalent peak levels of DNA-DNA interstrand cross-links.

¹ This investigation was supported by the Ben Kasle Flow Cytometry Facility of the Comprehensive Cancer Center of Metropolitan Detroit and USDHHS CA-22453.

² Supported by an award from the Belgian Work against Cancer. Present address: Radiotherapy, A.Z. V.U.B., Laarbeeklaan 101, 1090 Brussels, Belgium.

³ To whom requests for reprints should be addressed: Division of Hematology and Oncology, Wayne State University School of Medicine, P.O. Box 02188, Detroit, MI 48201.

Received 10/ 4/88. Revised 3/21/89. Accepted 3/28/89.

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